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Hyperargininemia

Argininemia

Hyperargininemia is a rare autosomal recessive disorder of the urea cycle. Deficiency of arginase, the enzyme necessary for the last step of the urea cycle, leads to progressive accumulation of arginine and the development of neurological symptoms after infancy, such as epilepsy, cognitive impairment, and spastic diplegia. In the absence of a timely recognition, the clinical presentation is progressive.


Presentation

Hyperargininemia is considered to be the least common urea cycle disorder (UCD) encountered in clinical practice, with estimated incidence rates of 1 in 350,000-1,000,000 [1]. The pathogenesis stems from mutations in genes coding for the catalytic enzyme arginase that is necessary for the conversion of L-arginine to urea and ornithine [2] [3]. Hyperargininemia, like the majority of UCDs, is transferred through an autosomal recessive pattern of inheritance, but the clinical presentation differs from other UCDs in terms of the onset of symptoms and their severity [2] [4]. Namely, patients mainly start to develop first signs after infancy, in the period between ages 2 and 4, while severe hyperammonemia that is typical in other UCDs is often absent [2] [4]. Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones [4] [5]. In the absence of proper therapy, more severe symptoms and signs are noted in a slowly progressive fashion - seizures (generalized tonic-clonic), progressive spastic diplegia, psychomotor and cognitive decline, as well as growth failure [1] [2] [4] [5]. In a subset of cases, episodes of vomiting and lethargy are observed [4]. Furthermore, liver diseases (cholestasis, liver failure, fibrosis, or even hepatocellular carcinoma) can be recognized in some cases of hyperargininemia [3] [6] [7].

Hepatosplenomegaly
  • In case 1, diagnosis was established at 2 months of age upon investigation of the etiology of cholestatic injury pattern and hepatosplenomegaly, and treatment was then initiated at when the patient was 3 months old.[ncbi.nlm.nih.gov]
  • Abdominal ultrasound confirmed the hepatosplenomegaly; the liver had homogeneous hyperechogenecity and intra- and extrahepatic bile ducts were normal.[journals.lww.com]
Uremia
  • Specific guanidino compounds, direct or indirect metabolites of arginine, are elevated in the blood of patients with uremia.[ncbi.nlm.nih.gov]
Irritability
  • Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones.[symptoma.com]
  • This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life. [ Read More ][icdlist.com]
  • This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of argininemia may be less severe, and may not appear until later in life.[wikidoc.org]
  • Infants may be irritable, vomit and exhibit feeding problems. They may be less alert when given cow's milk. Some infants may refuse to eat. Argininemia will affect the central nervous system.[thinkgenetic.com]
  • Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity).[accessanesthesiology.mhmedical.com]
Hyperactivity
  • Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity).[accessanesthesiology.mhmedical.com]
  • Hyperactivity. Behavior problems. Learning delays. Coma. Diagnosis: Genetic testing for argininemia is available. Genetic testing, also called DNA testing, looks for changes in the pair of genes that cause the condition.[medigoo.com]
  • They include: Avoiding foods high in protein or a dislike of meat Loss of appetite Nausea or vomiting Behavior problems, including hyperactivity Mental problems (confusion, delusions, hallucinations, psychosis ) Diagnosis Most newborns in the U.S. are[webmd.com]
  • […] trouble Tight, rigid muscles (called spasticity) Irritability Poor appetite Sleeping longer or more often Vomiting Weak muscle tone (called hypotonia) Breathing trouble Trouble regulating body temperature (your baby might get cold easily) Small head size Hyperactivity[babysfirsttest.org]
Hyperreflexia
  • The course and progression of symptoms should be assessed with the parents, whereas signs of upper motor neuron damage (hyperreflexia, spasticity) are hallmarks of hyperargininemia on a neurological exam.[symptoma.com]
Mental Deterioration
  • There was no clinical improvement, and spasticity of the lower and upper extremities was progressive with mental deterioration.[ncbi.nlm.nih.gov]

Workup

Because of the rather rare occurrence of hyperargininemia in clinical practice, the diagnosis might be difficult to attain without adequate clinical suspicion. For this reason, a thorough clinical investigation comprised of a meticulously obtained patient history and a detailed physical examination is of critical importance. The course and progression of symptoms should be assessed with the parents, whereas signs of upper motor neuron damage (hyperreflexia, spasticity) are hallmarks of hyperargininemia on a neurological exam [4]. Furthermore, ataxia, toe walking, and cognitive impairment may be noted [4]. Magnetic resonance imaging (MRI) of the endocranium is a useful procedure in the evaluation of patients suffering from hyperargininemia, showing both cerebral and cerebellar atrophy. Microcephaly could be present in some cases. Electroencephalography (EEG) is also an important component of the diagnostic workup [4], but in order to confirm hyperargininemia, biochemical or genetic testing is necessary. The measured activity of arginase will reveal abnormally low values [4] [5].

Treatment

  • In case 2, hyperargininemia was identified through newborn screening and treatment was started when patient was 21 days old. Cholestasis was only identified in the patient's further evaluation and it resolved 2 weeks into treatment.[ncbi.nlm.nih.gov]
  • Treatment, prenatal diagnosis and diagnosis through newborn screening are also discussed. (c) 2006 Wiley-Liss, Inc.[ncbi.nlm.nih.gov]
  • The Global Argininemia Treatment Market Research Report is an expert and inside and out analysis on the current state of Global Argininemia Treatment Market.[wboc.com]
  • Inborn metabolic diseases diagnosis and treatment (5th ed.). Berlin: Springer. ISBN 9783642157202. Retrieved 28 November 2016.CS1 maint: Extra text: authors list (link) Piña-Garza, J. Eric (2013).[en.wikipedia.org]
  • By these treatments, plasma and CSF concentrations of arginine showed a slight decrease, but were far above the normal range.[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis of Arginase Deficiency Disorder is generally good, so long as the necessary dietary restrictions are adhered to and proper medication is taken before symptom onset There are no preventive measures available for this disorder, as it is caused[dovemed.com]
  • Causes Differentiating Argininemia from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Argininemia usually becomes evident by about the age of 3.[wikidoc.org]
  • Long term prognosis of patients with arginninemia has not been well known, particularly for patients who are diagnosed prior to occurrence of neurological symptoms.[ashg.org]

Etiology

  • In case 1, diagnosis was established at 2 months of age upon investigation of the etiology of cholestatic injury pattern and hepatosplenomegaly, and treatment was then initiated at when the patient was 3 months old.[ncbi.nlm.nih.gov]
  • Chronic treatment consists of protein restriction along with nitrogen-scavenging medications. [1] Etiology Mutations in ARG1 lead to an unstable arginase enzyme, a protein found in the cytosol and responsible for the final step of the urea cycle.[statpearls.com]
  • The etiology of HHH syndrome begins with a mutation in the ornithine transporter gene, ORNT1, also called SLC25A15, whose product is a member of the solute mitrochondrial carrier protein family [ Camacho et al., 1999 ].[clinicalgate.com]

Epidemiology

  • Causes Differentiating Argininemia from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Argininemia usually becomes evident by about the age of 3.[wikidoc.org]
  • Another gene responsible for arginase can be found (ARG2); however, it is not translated in enough quantities to compensate the primary defect. [2] Epidemiology Arginase deficiency is the most uncommon urea cycle disorder.[statpearls.com]
  • A 2016 study suggests an adverse effect of arginase-1 deficiency on level 5 cortical motor neurons, as well as diminished synaptic transmission in a neonatal mouse model, recoverable by gene therapy. [3] Epidemiology Frequency United States The incidence[emedicine.com]
  • N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role.[ncbi.nlm.nih.gov]
  • Historical Perspective Classification Pathophysiology Genetics Argininemia has an autosomal recessive pattern of inheritance . Mutations in the ARG1 gene cause argininemia.[wikidoc.org]
  • No particular genotype-phenotype correlations have been postulated to date, meaning there is no accurate method to indicate a particularly affected population. [1] [3] Pathophysiology Arginase, commonly found in liver, erythrocytes, and salivary glands[statpearls.com]
  • Laemmle A, Gallagher RC, Keogh A, Stricker T, Gautschi M, Nuoffer JM, Baumgartner MR, Häberle J: Frequency and pathophysiology of acute liver failure in ornithine transcarbamylase deficiency (OTCD). PLoS One 2016;12;11:e0153358.[karger.com]

Prevention

  • In a patient with hyperargininemia, oral administration of sodium benzoate or phenylacetic acid together with an essential amino acid mixture was used to prevent hyperammonemia and to decrease plasma and CSF concentrations of arginine.[ncbi.nlm.nih.gov]
  • With this approach, further neurological deterioration is prevented and partial recovery of skills ensues. Early diagnosis of this disorder through newborn screening programs may lead to a better outcome.[ncbi.nlm.nih.gov]
  • Perioperative nutrition should aim for high carbohydrate intake and low protein intake to prevent arginine load. To prevent a catabolic state, avoid longer fasting periods and/or cover them with dextrose-containing intravenous solutions.[accessanesthesiology.mhmedical.com]
  • Most results were prevented by antioxidants and/or l‐NAME.[ingentaconnect.com]
  • The prognosis of Arginase Deficiency Disorder is generally good, so long as the necessary dietary restrictions are adhered to and proper medication is taken before symptom onset There are no preventive measures available for this disorder, as it is caused[dovemed.com]

References

Article

  1. Maramattom BV, Raja R, Balagopal A. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity. Ann Indian Acad Neurol. 2016;19(3):392-394.
  2. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84(3):243-251.
  3. Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47(9):1751-1762.
  4. Scaglia F, Lee B. Clinical, Biochemical, and Molecular Spectrum of Hyperargininemia Due to Arginase I Deficiency. Am J Med Genet C Semin Med Genet. 2006;0(2):113-120.
  5. Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607–610.
  6. Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion Tensor Imaging in Arginase Deficiency Reveals Damage to Corticospinal Tracts. Pediatr Neurol. 2010;42(1):49-52.
  7. Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap? Mol Genet Metab. 2004;81(Suppl 1):S38–S44.

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Last updated: 2019-06-28 12:04